Type I interferon (IFN) production by plasmacytoid dendritic cells (pDC) and increased expression of IFN- inducible genes are argued to be central to the pathogenesis of systemic lupus erythematosus (SLE). The type I IFN gene signature is associated with more severe disease in SLE and several other systemic and organ- specific autoimmune diseases. This suggests that there are significant disease subgroups in which less severe disease may be due to type I IFN independent mechanisms. The scarcity of experimental data on the mechanisms of type I IFN independent autoimmunity is a significant barrier to our understanding of the totality of the autoimmune disease process and its treatment. Our studies of the systemic autoimmunity resulting from exposure to mercury reveal the mild disease in this model to be independent of type I IFN. Mercury exposure in humans also results in a mild expression of systemic autoimmunity. Less fulminant systemic disease has also been observed with other xenobiotics and drugs. Thus mercury-induced autoimmunity may offer a suitable animal model to study type I IFN independent autoimmunity, the mechanisms of which may be applicable to multiple environmental agents. Based on our preliminary studies we hypothesize that in type I IFN independent autoimmunity innate immune responses are mediated by endosomal TLRs via NF-B activation leading to proinflammatory cytokine production and NF-B dependent synergy with IFN- resulting in enhanced expression of IFN- induced genes. We propose to address this hypothesis in four specific aims:- Aim 1) Are dendritic cells (DCs) essential for type I IFN independent autoimmunity?, Aim 2) Do endosomal Toll-like Receptor (TLR) signaling pathways mediate type I IFN-independent autoimmunity?, Aim 3) Is proinflammatory cytokine expression in type I IFN independent autoimmunity regulated by NF-B?, and Aim 4) Is proinflammatory IL-1 required for IFN- dependence of type I IFN independent autoimmunity? Answers to these questions will provide insight into the multiplicity of pathogenic pathways leading to systemic autoimmunity and broaden the conceptual foundation upon which autoimmune disease research is based.